The transient receptor potential (TRP) ion channel family is a group of ion channels located mostly in the plasma membrane of numerous human and animal cell types. There are about 28 TRP channels that share some structural similarity to each other. Many of these channels mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure and vision. In the body, some TRP channels are thought to be involved in thermosensation and to be used in animals to sense hot or cold. Some TRP channels are activated by the pungent ingredients of spices like garlic, chilli pepper, wasabi; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by drugs like cannabinoids, e.g. marijuana. Some act as sensors of cellular stress such as osmotic pressure, volume, stretch, and vibration.
Six protein families are comprised by the mammalian TRP superfamily: the classic TRPs (TRPCs), the vanilloid receptor TRPs (TRPVs), the melastatin or long TRPs (TRPMs), the mucolipins (TRPMLs), the polycystins (TRPPs), and ankyrin transmembrane protein 1 (ANKTM1, TRPA1). With the exception of some polycystins, TRPs are generally assumed to have six transmembrane domains. The TRP channels are a family of ion channel proteins that mediate ion influx of Na+ and Ca2+ and, in several cases, Mg2+ and other divalent cations. Since TRPs are intimately linked with intracellular Ca2+ signaling, they are implicated in the control of cell cycle progression, cell migration, and programmed cell death.
The TRPM subfamily comprises eight members, including the cold and menthol receptor TRPM8, also designated as TRP melastatin 8, cold and menthol receptor 1 (CMR1) or transient receptor potential cation channel subfamily M member 8. In 2002, using divergent approaches, two scientific groups simultaneously identified and described TRPM8 (McKemy D D et al., Nature 2002, 416(6876):52-58; Peier A M et al., Cell 2002, 108(5):705-15). The channel is expressed, e.g., in small-diameter primary sensory neurones, where it presumably functions as a thermosensor. TRPM8 consists of six putative transmembrane spanning segments, a pore-forming loop and intracellularly located NH2 and COOH termini. Assembly of channel subunits as tetramers results in the formation of cation-selective channels that permeate calcium ions. TRPM8 is involved in the detection of sensations such as coolness triggered, inter alia, by cooling agents and/or by cold (i.e. temperatures ranging from about 8° C. to about 28° C.).
Cooling agents are used extensively by flavor and fragrance suppliers in order to evoke associations with freshness and cleanliness. Hence, over the last 30 years a considerable number of compounds have been synthesized and evaluated for the physiological sensation of “cooling”. For instance, the international patent application WO 2010/017609 discloses the use of the ingredients of Mentha and Eucalyptus oil as antiperspirants, the ingredients presumably acting as TRPM8 agonists. Furthermore, menthol, a cyclic terpene alcohol found in leaves of the genus Mentha, is used in a wide range of products, such as confectionary, candy, toothpastes, vaporubs, and aromatherapy inhalations. When applied at low concentrations to the skin or the oral mucosa, menthol elicits a pleasant cool sensation, while higher doses can cause burning, irritation, and pain.
It is known in the art that menthol can act as natural modulator of TRPM8 (McKemy D D et al., Nature 2002, 416(6876):52-58; Peier A M et al., Cell 2002, 108(5):705-15; McKemy D D, Molecular Pain 2005, 1:16). Upon activation, a signal transduction cascade is mediated by TRPM8, producing the perception of cold in the nervous system. For instance, activation of TRPM8 can induce an increase of intracellular calcium ions in cold-sensitive neurones. This calcium influx subsequently produces an inward current that provokes cold sensing.
In addition to menthol, a number of further cooling agents, including icilin (also designated as AG-3-5), Cool-actP, Cooling Agent 10, FrescolatMGA, FrescolatML, geraniol, hydroxycitronellal, linalool, PMD38, WS-3, and WS-23 are known in the art to activate TRPM8 in vitro (McKemy D D et al., Nature 2002, 416(6876):52-58; Weil A et al., Mol. Pharmacol. 2005, 68(2):518-27; Behrendt H J et al., Br. J. Pharmacol. 2004, 141(4):737-45). Of these icilin, was first identified as a super-cooling agent in the early 1980s and bears little resemblance to menthol structurally (WO 2004/026840).
A number of methanol derivatives or other cooling agents which may exhibit a similar action at TRPM8 are known in the art. For instance, the international patent application WO 2010/026094 relates to modulators of TRPM8, to a method of modulating the TRPM8 channel, to the use of the modulators for inducation of cold sensation and to the objects and means produced using said modulators. High concentrations of menthol can trigger other ion channels (e.g. TRPA1), presumably leading to these unpleasant sensations through activation of nociceptive sensory neurons (see e.g. review by McKemy D D, Mol. Pain 2005, 1:16). In addition menthol has a typical flavour and aroma which sometimes is disadvantageous for industrial applications in the food and cosmetic industry. Hence, there is a need for compounds which selectively modulate TRPM8, e.g. compounds which exhibit distinct activation concentrations at TRPM8 and TRPA1.
TRPA1 is a member of the TRPA branch of the TRP ion channel gene family. TRPA1 was identified as a potential mediator of noxious cold stimuli in nociceptive sensory neurons. Moreover, recent studies found evidence that TRPA1 is involved in sensory neural responses to mustard oil, allicin, and other chemical irritants (Jordt S E et al., Nature 2004, 427(6971):260-65; Bandell M et al., Neuron. 2004, 41(6):849-57). Hence, TRPA1 channels respond to a multitude of irritants with diverse origins and chemical structures, leading to, amongst others, sensations of pain, coughing, apnea, and lachrymation.
Some of the above-mentioned cooling agents have cooling effects at least to some extents, but may be insufficient and unsatisfactory in the retainability of the cooling effect. Hence, there is a strong demand in the art for providing cooling agents that have an improved sensory stimulating effect. Furthermore, some of the cooling agents known in the art may be insufficient with regard to their efficacy, their period of action, their scent, their taste, their solubility, and/or their volatility, and/or may cause irritation of the mucous membranes, itching of skin, tearing and/or the urge to cough. Accordingly, there is a need for alternative cooling agents that may overcome one or more of these drawbacks.